MedChem

Imipramine 

What is important to know about imipramine?

• pharmacophore: dihydrodibenzoazepine

• propyl side chain + tertiary amine → lipophilicity

  • can undergo meatbolic conversion to secondary amine → desipramine (both active)

• non-selective b/w NET and SERT

Despiramine 

What is important about desipramine? 

• pharmacophore: dihydrodibenzoazepine

• secondary amine 

  • makes it more selective to NET

  • better oral bioavailability and less ADEs

  • less lipophilic → less into CNS, why less ADEs 

Clomipramine 

What is important about clomipramine?

• pharmacophore: dihydrodibenzoazepine

  • + Cl → enhances binding affinity and lipophilicity 

• more potent than imipramine 

• tertiary amine 

  • can be converted to secondary amine and still active - metabolite more selective to NET 

• can inhibit DAT

Amitriptyline

What is important about amitriptyline?

• pharmacophore: dibenzocycloheptene

  • no nitrogen - all carbons in center ring

  • same pharmacological activity

• light sensitive due to double bond

• tertiary amine 

  • can be converted to secondary amine → nortriptyline 

Nortriptyline

What is important about nortriptyline?

• pharmacophore: dibenzocycloheptene

  • no nitrogen - all carbons in center ring

  • same pharmacological activity

• light sensitive due to double bond

• secondary amine → more selective to NET 

  • less lipophilic, so less CNS and less ADEs 

Timipramine

What is important about trimipramine? 

• pharmacophore: dihydrodibenzoazepine

  • imipramine derivative

• shorter half-life compared to imipramine due to branched methyl 

  • creates a stereocenter (both active) 

  • decreases binding affinity to NE and 5-HT receptors

• tertiary amine 

  • can be metabolized to secondary that is more selective to NET 

Doxepin

What is important about doxepin? 

• dibenzeoxepin derivative

  • added O → creates diastereomers (E better activity)

  • E-isomer more selective to NET

• lower binding affinity versus imipramine 

• tertiary amine

  • can be converted to secondary amine more selective to NET

Maprotiline

What is important about maprotiline? 

• tetracyclic anthracene derivative 

  • central ring structure is a bicyclic ring 

• secondary amine → selective to NET 

  • convert to primary and weak/little activity 

What causes TCA mediated toxicities?

• epoxide metabolites (tertiary or secondary amines)

  • are electrophiles and react with cellular proteins that can trigger an immune response → hypersensitivity reactions in susceptible patients 

What helps bind TCAs with SERT?

• at physiological pH, tertiary amine undergoes protonation

  • allows for ionic interaction with aspartic acid in binding site → locks molecule in place 

What is the SAR of TCAs?

• central ring structure - 3 rings, 2 of which are benzene 

  • ring B (center) tolerates carbon, nitrogen and oxygen atoms @ C10/C11 

  • halogens @C3/7 enhance SERT selectivity 

• 3 carbon spacer (propyl) @C/N5 necessary 

  • increase or decrease length decreases or loses activity 

• amines

  • tertiary → inhibits SERT/NET, reduced oral bioavailability 

  • secondary → NET selective, superior oral bioavailability to tertiaries, reduced ADEs  

Why do halogens at C3/7 position enhance SERT selectivity?

• halogen can interact with protonated amine group

  • locks into a bioactive conformation which favours SERT

  • improves activity and potency 

Trazodone

What is important about trazodone? 

• pharmacophore: phenylpiperazine 

  • chlorobenzene → more lipophilic, more into CNS

  • piperazine → enhances oral bioavailability

• fused bicyclic ring structure = triazole + benzene

  • enhances binding affinity 

What are the concerning metabolites of trazodone and why?

• epoxide metabolite (off benzene fused ring) 

  • can cause hypersensitivity and hepatotoxicity 

• If loses propyl group + fused rings → iminoquinone 

  • electrophile/oxidant, and can cause cellular damage and toxicity

Mianserin

What is important about mianserin? 

• pharmacophore: benzoazepine

• tetracyclic

  • benzene + benzene + 7 member ring + piperazine 

  • benzene had poor oral bioavailability and caused ADEs like glucopenia 

• had to do SAR, could not continue using 

Mirtazapine

What is important about mirtazapine? 

• pharmacophore:  benzoazepine 

• tetracyclic 

  • benzene + pyridine + 7 member ring + piperazine 

  • changing benzene to pyridine → less lipophilic, more bioavailable and less ADEs 

• “considered most effective antidepressant”

Lithium carbonate

Lithium citrate

What is important about lithium carbonate and lithium citrate?

• inorganic molecules (cations) 

  • monovalent cation → other cations replaced with Li, most times bind more efficiently 

  • adenylyl cyclase has Mg+, when replaced limits activity → reduces cAMP in brain

  • replaces Na+ in GCPR, prevents activation 

• narrow therapeutic index 

Fluvoxamine

What is important about fluvoxamine?

• 2-aminoethyl oxime derivative 

  • primary amine → protonation will intaact with aspartic acid in binding site of SERT 

• trifluoromethyl (EWG) @ para position

  • enhances binding affinity to SERT  

• E-isomer active

  • double bond = light sensitive → light will convert to Z and decrease activity 

Fluoxetine

What is important about fluoxetine? 

• phenoxyphenylalkylamine derivative

  • 2 benzenes make it highly lipophilic

• trifluoromethyl (EWG) @ para position (lipophilic) 

  • enhances binding affinity to SERT

• stereocenter → is a racemic mixtiure

  • S-enantiomer has better activity 100x more

• very lipophilic → long half-life (24-72h)

• secondary amine

  • can be converted to primary amine → norfluoxetine and still be active long half-life (4-16 days) 

Paroxetine 

What is important about paroxetine? 

• pharmacophore: phenylpiperidine 

• Fluorine (EWG) @ para position 

• dioxolane → enhances oral bioavailability compared to fluoxetine 

• 2 stereocenters → Trans is active 

• secondary amine 

  • NO metabolism to other amine metabolites 

• more potent to SERT than fluoxetine 

Sertraline 

What is important about sertraline?

• pharmacophore: phenylalkylamine 

• dichlorobenzene, Cl @3 & 4

  • enhance binding affinity by interacting with halogen binding pocket in SERT (most potent SERT inhibitor)

  • increase lipophilicity

• poor oral bioavailability to others 

• 2 stereoisomers → Cis geometry active, enhances binding affinity

• secondary amine 

  • converts to primary, but weaker activity 

Citalopram

What is important about citalopram?

• pharmacophore: benzofuran 

• Fluorine and cyanide (EWGs) @ para positions

  • enhance binding affinity  

• racemic mixture where S-stereoisomer only is active = escitalopram 

• tertiary amine 

  • converted to secondary and primary, both have weak activity 

Escitalopram 

What is important about escitalopram? 

• pharmacophore: benzofuran 

• Fluorine and cyanide (EWGs) @ para positions

  • enhance binding affinity  

• only S-stereoisomer

• tertiary amine 

  • converted to secondary and primary, both have weak activity 

What is the SAR of SSRIs?

• need a hydrophobic (lipophilic) region 

  • fluorophenyl, dichloromethyl, alkylmethoxy 

• positive ionizable, polar regions - to bind with aspartic acid 

  • secondary or tertiary amine 

• aromatic rings with substituted EWGs 

Venlafaxine

What is important about venlafaxine?

• methoxyphenylethylamine derivative

• racemic mixture 

• tertiary amine 

  • secondary amine is NOT active

• methoxy (EDG) @ para position 

• short half-life b/c poor bioavailability due to rapid first pass effect 

  • major metabolite → oxidized aromatic ring to phenol group = desvenlafaxine - better activity, longer half-life and potency 

    • further conjugated to secondary amine, no longer active 

  • minor metabolite - secondary amine 

Desvenlafaxine

What is important about desvenlafaxine?

• methoxyphenylethylamine derivative

• racemic mixture 

• tertiary amine 

  • secondary amine is NOT active

• methoxy (EDG) @ para position 

• Active metabolite of venlafaxine (phenol vs methoxybenzene)

  • better activity, bioavailability, longer half-life and potency

• 30x more potent of SERT vs NET

Duloxetine

What is important about duloxetine?

• pharmacophore: naphthalene 

  • increases lipophilicity and CNS activity 

  • derived from fluoxetine

• thiophene → enhances binding affinity 

• secondary amine 

  • primary weak activity 

• S-enantiomer is active

Bupropion

What is important about bupropion? 

• pharmacophore: phenyl-tert-butylamine

  • tertiary butyl group → increases lipophilicity

  • Chlorine substituent on phenyl → enhances ability to get into CNS

• racemic mixture → similar activity 

• considered prodrug 

  • poor oral bioavailability due to extensive and RAPID metabolism

• metabolites, both active:

  • hydroxybupropion → methyl oxidized to alcohol

  • hydrobupropion → ketone converted to hydroxy (causes insomnia and dry mouth) 

Diazepam

What is important about diazepam?

• pharmacophore: 1,4-benzodiazepines 

• Cl @ C7 → increases lipophilicity and binding affinity 

• benzene @ C5 → increases lipophilicity and CNS conc 

• tertiary amine 

  • metabolized to active secondary amine → long half-life 

  • primary amine NOT active

Clonazepam 

• pharmacophore: 1,4-benzodiazepines 

• nitrogen dioxide (EWG)@ C7 → increases lipophilicity and binding affinity 

• benzene @ C5 → increases lipophilicity and CNS conc 

  • with ortho Cl substituent → enhances binding affinity 

• secondary amine 

  • metabolized primary amine which is NOT active

Lorazepam 

• pharmacophore: 1,4-benzodiazepines 

• Cl @ C7 → increases lipophilicity and binding affinity 

• benzene @ C5 → increases lipophilicity and CNS conc 

  • with ortho Cl substituent → enhances binding affinity 

• hydroxy @ C3 → more polar, faster elimination due to phase II conjugation reactions (glucuronidation)

• secondary amine 

  • metabolized primary amine which is NOT active

Bromazepam 

• pharmacophore: 1,4-benzodiazepines 

• Br @ C7 → increases lipophilicity and binding affinity 

• pyridine@ C5 → less lipophilic  

• tertiary amine 

  • metabolized to active secondary amine → long half-life 

  • primary amine NOT active

Alprazolam

What is important about alprazolam?

• pharmacophore: 1,4-benzodiazepines 

• Cl @ C7 → increases lipophilicity and binding affinity 

• benzene @ C5 → increases lipophilicity and CNS conc 

• fused triazole → enhances oral bioavailability 

  • short acting b/c now substrate of 3A4

What is the SAR for benzodiazepines?

• 1,4-benzodiazepine ring essential for activity

• N-1 position tolerate alkyl groups

• N4-C5 double bond necessary

• ring A and C can be phenyl or heterocyclic

• need EWG @ C7

• EWG at ortho/diortho on ring C increase activity

Phenelzine 

What is important about phenelzine? 

• hydrazine group → causes hepatotoxicity 

• covalently binds with MAO-A and MAO-B  (irreversible, nonselective binding)

Tranylcypromine

What is important about tranylcypromine? 

• nonhydrazine amphentamine derivative 

• covalently binds with MAO-A and MAO-B (irreversible, nonselective binding)

Moclobemide

What is important about moclobemide?

• nonhydralazine benzamide derivative

• pharmacophore: morpholine 

  • increases oral bioavailability due to enhancing PK properties 

• selective reversible inhibitor of MAO-A

  • time-dependent complex with MAO-A 

Why can irreversible MAOIs cause hypertensive crisis and not reversible MAOIs?

• irreversible MAOIs covalently bind with MAO-A, which tyramine requires for metabolism to inactive metabolite

  • causes accumulation of tyramine, which acts as a “false NT” b/c structurally similar to NE and DA → activates alpha1 receptors → vasoconstriction → HTN crisis

• In contrast, reversible MAOIs do not permanently inhibit MAO-A

  • tyramine has higher affinity for MAO-A than moclobemide, so will be replaced 

  • allowing for periodic metabolism of tyramine, thereby reducing the risk of hypertensive crises